Isoflurane-enhanced recovery of canine stunned myocardium - Role for protein kinase C?

Background: Isoflurane enhances the functional recovery of postischemic, re perfused myocardium by activating adenosine A, receptors and adenosine trip hosphate-regulated potassium channels. Whether protein kinase C is involved in this process is unknown. The authors tested the hypothesis that inhibit ion of protein kinase C, using the selective antagonist bisindolylmaleimide , attenuates isoflurane-enhanced recovery of stunned myocardium in dogs. Methods: Fifty dogs were randomly assigned to receive intracoronary vehicle or bisindolylmaleimide (2 or 8 mu g/min) in the presence or absence of iso flurane (1 minimum alveolar concentration). Five brief (5 min) coronary art ery occlusions interspersed with 5-min reperfusion periods followed by 180 min of final reperfusion were used to produce myocardial stunning. Hemodyna mics, regional segment shortening, and myocardial-blood flow (radioactive m icrospheres) were measured at selected intervals. Results: There were no differences in baseline hemodynamics, segment shorte ning, or coronary collateral blood flow between groups. Isoflurane signific antly (P < 0.05) decreased heart rate, mean arterial pressure, rate pressur e product, and the maximum rate of increase of left ventricular pressure (dP/dt(max)) in the presence or absence of bisindolylmaleimide. Sustained co ntractile dysfunction was observed in dogs that received vehicle (recovery of segment shortening to 12 +/- 8% of baseline), in contrast to those that received isoflurane (75 +/- 7% recovery). Bisindolylmaleimide at a dose of 2 mu g/min alone enhanced recovery of segment shortening (50 +/- 7% of base line) compared with vehicle-pretreated dogs, and isoflurane in the presence of 2 mu g/min bisindolylmaleimide further enhanced recovery of contractile function (79 +/- 8% of baseline). in contrast, 8 mu g/min bisindolylmaleim ide alone (32 +/- 12%) or combined with isoflurane (37 +/-. 17%) did not en hance recovery of segment shortening compared with vehicle-pretreated dogs. Conclusions: The results indicate that protein kinase C inhibition using lo w doses of bisindolylmaleimide alone produces cardioprotection, and isoflur ane further enhances this protection. In contrast, high doses of bisindolyl maleimide are not cardioprotective in the presence or absence of isoflurane . A role for protein kinase C during isoflurane-induced recovery of the stu nned myocardium cannot be excluded.